Cardiorenal Interactions Research Articles

FGF-23 and Cardio-Renal Interactions in Heart Failure

Background Fibroblast growth factor-23 (FGF-23) is a phosphaturic hormone with a primary role in the regulation of phosphate homeostasis. Recently, FGF-23 was shown to be a strong predictor of cardiovascular outcomes, and animal models have reported multiple non-phosphaturic, or off-target, effects of FGF-23. Some of the negative cardio-renal actions reported in the literature are adverse left ventricular remodeling, induction of inflammation, renal/cardiac fibrosis, and direct effects on renal sodium retention. The aim of this current investigation was to further explore the association between FGF-23 with various parameters of cardio-renal dysfunction. Hypothesis FGF-23 will be associated with cardio-renal parameters such as inflammation, neurohormonal activation, diuretic responsiveness, and survival. Methods We analyzed plasma FGF-23 levels in 199 outpatient heart failure (HF) patients who underwent diuretic administration followed by timed urine collections. Diuretic response was defined as the sodium output per doubling of the diuretic dose. Results Higher levels of FGF-23 tended to correlate with serum phosphate (r=0.21, p=0.09) but were not correlated with serum calcium (p=0.37). There were stronger correlations between FGF-23 and several parameters of cardio-renal dysfunction including lower eGFR (r=-0.42, p 0.3 for both). Higher levels of FGF-23 predicted worse diuretic responsiveness (r=-0.47, p Conclusion In patients with HF, plasma levels of FGF-23 were associated with multiple metrics of cardio-renal dysfunction, including a strong independent association with diuretic responsiveness and mortality. Additional research is warranted to understand if FGF-23 is a marker or mediator of cardio-renal dysfunction and if interventions to lower FGF-23 levels can improve outcomes.

Urine Growth Differentiation Factor-15 is Not an Independent Biomarker of Cardio-Renal Interactions in Patients with Heart Failure

Introduction Growth differentiation factor-15 (GDF-15) is a stress-responsive biomarker that is elevated in patients with heart failure (HF) and carries prognostic value. However, conditions other than HF can increase levels, making plasma concentration non-specific for HF. In diabetic patients, urinary GDF-15 has been associated with worse kidney function, but its role in HF remains unknown. Therefore, we sought to determine if urinary GDF-15 might provide unique cardio-renal information in patients with HF. Hypothesis Urinary GDF-15 will be associated with diuretic efficiency and survival, independently of plasma GDF-15. Methods GDF-15 was measured in 171 patients with heart failure treated with IV diuretics in the outpatient setting. Pre and post diuretic spot urinary GDF-15 (n=166) was measured using the Mesoscale Assay platform (MesoScale Diagnostics, Gaithersburg, MD, USA). Urinary GDF-15 was normalized to urine creatinine. Diuretic efficiency was defined as sodium excretion per doubling of loop diuretic dose. Results Plasma GDF-15 was weakly correlated with pre-diuretic urinary GDF-15 (r= 0.21, p=0.019) and modestly correlated with post-diuretic urinary GDF-15 (r=0.50, p Conclusion Plasma, but not urinary, GDF-15 was independently associated with diuretic efficiency and survival. This suggests that urinary GDF-15 does not provide specific cardio-renal information, likely because it is mainly filtrated from plasma rather than produced in the kidney.

452-P: Albumin/Creatinine Ratio and Pulse Wave Velocity Predicts Coronary Artery Disease and Renal Outcome in Type 2 Diabetic and Prediabetic Subjects

Introduction: Silent coronary heart disease is frequently undetected in type 2 diabetes mellitus (DM2) and prediabetes determined by glucose intolerance (GI). Pulse wave velocity (PWV) and albumin-creatinine ratio (ACR) have been considered markers of cardiovascular mortality, coronary heart disease and chronic renal failure. Aims: To evaluate the incidence of coronary heart disease (CHD) and its relationship with urinary albumin-creatinine ratio, glomerular filtration rate (GFR) and PWV in type 2 DM with silent CHD. Methods: We analyzed 92 individuals (44 male), 49 (60±7y) type 2 DM non-insulin dependents and 43 prediabetics (43±4y), with Grade I-II hypertension and no symptoms of CHD. All type 2 DM patients were under hypoglycemic treatment with an A1C hemoglobin between 5.5 and 6.5%. Every patient underwent a myocardial perfusion SPECT scan. In those subjects with ischemic patterns, a coronary angiography was performed. In addition, a PWV, glomerular filtration rate (CrCl), and ACR were evaluated. Statistics: mean±SEM, and ANOVA followed by Post Hoc analysis among groups. Results: Silent CHD was found in 48.59% of DM2 and 25.58% of GI. DM2 and GI patients with CHD had higher ACR and PWV and reduced glomerular filtration rate (p<0.05). DM2 and GI showed a negative relationship between GFR and ACR (p<0.05). Type 2 diabetic and GI showed a negative relation between GFR and ACR or PWV when having GFR above 60 mil.min. Meanwhile, in type 2 Diabetics with CHD and GFR < 60 ml.min a negative relationship with PWV was only, suggesting a cardiorenal interaction in type 2 diabetes. Conclusions: Higher PWV, lower GFR and ACR predict the incidence of CHD in DM2. GI also represent a group of higher risk for coronary heart disease with the same predictors showed in DM2. PWV seems to represent a reliable marker. Disclosure R.A. Sanchez: None. M.J. Sanchez: None. A.J. Ramirez: None.

Cholinergic Stimulation Modulates Kidney Cellular Immune Response Triggered by Myocardial Infarction in Rats

There is a close relationship between cardiac and renal function, several studies have shown that cardiorenal interactions occur in both directions. Acute myocardial infarction (AMI) has a significant influence on renal function. Changes in renal function may be due to neurohumoral adaptations, reduction of renal perfusion, increase of renal venous pressure and right ventricular dysfunction. More recently, interest has shifted to the role of inflammation in the development of renal lesions. An increase of parasympathetic activity seems to promote changes in the mobilization of inflammatory cells, such as macrophages and lymphocytes. The role of the parasympathetic nervous system in immune cells is known as “Cholinergic anti‐inflammatory pathway”. Previous studies by our group have demonstrated that increased vagal activity through administration of pyridostigmine (PY) (acetylcholinesterase pharmacological antagonist) reduces early inflammatory process in myocardial tissue after AMI in normotensive rats, but little is known about vagal modulation and renal inflammation.ObjectiveThe aim of this study was to assess the effects of cholinergic stimulation on the modulation of the cellular immune response triggered by AMI in spontaneously hypertensive rats (SHR).Material and MethodsSixteen SHR male rats were randomly assigned to three groups: SHAM group: S (n = 5), infarcted group: I (n = 6) and infarcted and treated group: I + PY (n = 5). All the animals were anesthetized and submitted to thoracotomy and the infarcted and infarcted and treated groups were subjugated to left coronary artery ligation. Treatment with PY started one hour after the infarction, extending until day 7. The rats were cannulated in the left femoral artery to record blood pressure on the day 6. On day 7, the animals were euthanized and submitted to organ perfusion and fixation, for immunohistochemical analysis of macrophages (CD‐68+) and lymphocytes (CD3+) in renal tissue. Marked cells were counted in 10 fields including glomerulus and interstitium (Nikon 400x). Statistical analysis was performed using GraphPad Prism and one‐way analysis of variance (ANOVA). Values of p> 0.05 were considered statistically significant.ResultsThe I + PY group showed less CD68+ macrophages and more CD3+ T lymphocytes in the renal parenchyma if compared to S and I groups, p = 0.04 and p = 0.04, respectively. The mean levels of systolic blood pressure, diastolic blood pressure and mean arterial pressure found for the I + PY group was lower when compared to the pressure levels found in the other groups.ConclusionCholinergic stimulation using PY was able to quantitatively modify CD68+ macrophages and CD3+ lymphocytes in the renal tissue of rats during the acute phase of the experimental model of AMI. In addition, changes in hemodynamic characteristics were observed with the treatment of this anticholinesterase, suggesting possible protective effects of its vagal immunomodulation.Support or Funding InformationConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Total amount of CD3+ lymphocytes found in the 10 renal fields for the analyzed groupsimageTotal amount of CD3+ lymphocytes found in the 10 renal fields for the analyzed groups Total amount of CD68+ macrophages found in the 10 renal fields for the analyzed groupsimageTotal amount of CD68+ macrophages found in the 10 renal fields for the analyzed groupsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hypervolemic Hyponatremia in Heart Failure.

Heart failure (HF) represents the most common cause of hypervolemic hyponatremia in current clinical practice. The presence of hyponatremia has been independently associated with worse outcomes in this patient population. The pathogenesis of hyponatremia in HF involves complex neurohormonal and cardio-renal interactions, including an increase in non osmotic secretion of arginine vasopressin (AVP) and insufficient tubular flow in the diluting segments of the nephron. The treatment of hyponatremia in HF involves decongestant therapy with diuretics, neurohormonal blockade and in certain occasions the use of AVP antagonists. The aim of this chapter is to summarize the pathophysiology, current evidence, and management recommendations for hyponatremia in patients with HF, with a specific focus on AVP homeostasis.

Cardiorenal Syndrome Revisited.

Cardiorenal syndromes have been categorized into 5 clinical subtypes based on which organ is perceived to be the primary precipitant of the vicious and interrelated cycle of declining function in both organs. This clinical classification has broadened interest in cardiorenal interactions, but it is merely descriptive, does not rely on or inform predominant pathophysiology, and has produced little change in either practice or the research agenda. In contrast, recent scientific work identifies common pathophysiological pathways for several categories of cardiorenal syndromes, suggesting a unifying pathogenesis. Fibrosis is a common consequence of inflammation- and oxidative stress-related endothelial dysfunction in aging, hypertension, diabetes mellitus, obesity, ischemia, and organ injury. It is a common feature in heart failure and chronic kidney disease. Therefore, we suggest that fibrosis may be not only a marker but also the primary driver of pathophysiology in several cardiorenal syndromes. Interstitial fibrosis in the heart, large arteries, and kidneys may play a key role in the pathophysiology of the cardiorenal syndrome continuum. Focusing on fibrosis as a disease mediator might enable the identification of fibrosis-related biotargets that could potentially be modulated with renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, or other novel antifibrotic agents in development. This conceptual approach may be an effective new strategy for the prevention and treatment of fibrosis within the cardiorenal syndrome continuum.

Cardiorenal Interactions Revisited: How to Improve Heart Failure Outcomes in Patients With Chronic Kidney Disease

To summarize current advances in the understanding and management of heart failure (HF) in patients with advanced chronic kidney disease (CKD). Diagnosis of HF and treatment of congestion are crucial in the management of patients with advanced CKD to reduce symptoms, preserve organ function, and improve outcomes. Echocardiography and cardiovascular biomarkers may help to differentiate cardiac from non-cardiac components of overhydration. Renal replacement therapy or ultrafiltration may be required to treat congestion. Furthermore, patients with advanced CKD are frequently undertreated with disease-modifying HF therapies, but the use of beta-blockers and ACEi should be considered under close monitoring of kidney function and serum potassium. The use of the new oral potassium binders may translate into improved outcomes. The treatment of HF in patients with advanced CKD requires a multi-disciplinary approach. New diagnostic and therapeutic strategies are under evaluation and may contribute to improved outcomes.

Volume-Kidney Interaction in Chronic Heart Failure - Impact of Subclinical Volume Expansion and Chronic Kidney Disease on Clinical Outcomes

ObjectivesAssess the impact of volume-kidney interactions on outcomes in clinically “euvolemic” chronic heart failure (HF) patients with co-existing chronic kidney disease (CKD).BackgroundCardio-renal interactions are complex and bi-directional and may in part be mediated by the extent of intravascular volume overload. The impact of subclinical volume expansion on outcomes in HF patients with CKD has not been previously examined.MethodsPlasma volume (PV) was prospectively measured in 110 stable HF patients with varying degrees of CKD using a standardized radiolabeled albumin indicator-dilution technique. To examine the interactive roles of volume expansion and CKD the cohort was dichotomized by median PV and then further stratified by cohort median creatinine (sCr), eGFR, and BUN and analyzed for outcomes of HF-related mortality or 1st hospitalization using Kaplan-Meier method.ResultsSubclinical volume overload was demonstrated in 76% of the cohort. Over 1.5 years, sCr and BUN above and eGFR below (Fig.) cohort median values identified highest risk for the composite end-point but only in severe PV expansion (≥ median expansion of +26%) (p=0.02). In normal to moderate PV expansion (< +26% expansion) worse renal function was not associated with increased risk (p=0.578).ConclusionsIn clinically stable chronic HF patients with co-existing CKD, subclinical PV expansion is common, and importantly the extent of PV expansion impacts outcomes including early HF mortality. However, better kidney function mitigates the deleterious effects of severe PV expansion, while mild-moderate expansion balances the risks of worse renal function. Thus, volume-kidney interactions are complex with volume status modulating the impact of CKD on outcomes in chronic HF. Figures. Risk Stratification by Median eGFR in Chronic Heart Failure Patients with A. Severe Plasma Volume Expansion (PV ≥ Median of +26% Above Normal Volume) B. Mild-Moderate Plasma Volume Expansion (PV < Median of +26% Above Normal Volume) Assess the impact of volume-kidney interactions on outcomes in clinically “euvolemic” chronic heart failure (HF) patients with co-existing chronic kidney disease (CKD). Cardio-renal interactions are complex and bi-directional and may in part be mediated by the extent of intravascular volume overload. The impact of subclinical volume expansion on outcomes in HF patients with CKD has not been previously examined. Plasma volume (PV) was prospectively measured in 110 stable HF patients with varying degrees of CKD using a standardized radiolabeled albumin indicator-dilution technique. To examine the interactive roles of volume expansion and CKD the cohort was dichotomized by median PV and then further stratified by cohort median creatinine (sCr), eGFR, and BUN and analyzed for outcomes of HF-related mortality or 1st hospitalization using Kaplan-Meier method. Subclinical volume overload was demonstrated in 76% of the cohort. Over 1.5 years, sCr and BUN above and eGFR below (Fig.) cohort median values identified highest risk for the composite end-point but only in severe PV expansion (≥ median expansion of +26%) (p=0.02). In normal to moderate PV expansion (< +26% expansion) worse renal function was not associated with increased risk (p=0.578). In clinically stable chronic HF patients with co-existing CKD, subclinical PV expansion is common, and importantly the extent of PV expansion impacts outcomes including early HF mortality. However, better kidney function mitigates the deleterious effects of severe PV expansion, while mild-moderate expansion balances the risks of worse renal function. Thus, volume-kidney interactions are complex with volume status modulating the impact of CKD on outcomes in chronic HF. Figures. Risk Stratification by Median eGFR in Chronic Heart Failure Patients with A. Severe Plasma Volume Expansion (PV ≥ Median of +26% Above Normal Volume) B. Mild-Moderate Plasma Volume Expansion (PV < Median of +26% Above Normal Volume)

Practical management of concomitant acute heart failure and worsening renal function in the emergency department.

Worsening renal function (i.e. any increase in creatinine or decrease in the estimated glomerular filtration rate) is common in patients admitted for acute heart failure in the emergency department. Although worsening renal function (WRF) has been associated with the occurrence of dismal outcomes, this only appears to be the case when associated with clinical deterioration. However, if the clinical status of the patient is improving, a certain increase in serum creatinine may be acceptable. This WRF, which is not associated with clinical deterioration or adverse outcomes (e.g. during treatment up-titration), has been referred to as 'pseudo-WRF' and should not detract clinicians from targeting 'guideline-recommended' therapies. This is an important message for emergency physicians to pursue diuretics as long as signs of pulmonary congestion persist to improve the clinical status of the patient. In the present review, we aim to provide clinicians in acute settings with an integrative and comprehensive approach to cardiorenal interactions in acute heart failure.

Associations Between Kidney Disease Measures and Regional Pulse Wave Velocity in a Large Community-Based Cohort: The Atherosclerosis Risk in Communities (ARIC) Study

Arterial stiffness is suggested as a mediator of cardiorenal interaction. However, previous studies reported inconsistent associations between chronic kidney disease (CKD) and arterial stiffness and were limited byusing either estimated glomerular filtration rate(eGFR) or albumin-creatinine ratio (ACR) and examining arterial stiffness at limited segments. Cross-sectional. 3,424 Atherosclerosis in Communities (ARIC) Study participants aged 66 to 90 years during 2011 to2013. eGFR and ACR. Pulse wave velocity (PWV) at 6 segments: carotid-femoral (cfPWV), heart-carotid (hcPWV), and heart-femoral (hfPWV), reflecting central stiffness; heart-ankle (haPWV) and brachial-ankle (baPWV), representing both central and peripheral stiffness; and femoral-ankle (faPWV), indicating peripheral stiffness. Multiple linear and logistic regression models to quantify the associations ofeGFR and ACR with continuous PWV andelevated PWV (in the highest quartile), respectively. After adjusting for age, sex, and race, higher cfPWV and hfPWV were consistently associated with lower eGFR and higher ACR. Higher haPWV and baPWV were also observed with higher ACR. The independent association of both CKD measures with elevated cfPWV remained consistent after adjusting for additional confounders (ORs of elevated cfPWV were 1.09 [95% CI, 1.01-1.18] per 15-mL/min/1.73m2 lower eGFR and 1.20 [95% CI, 1.07-1.33] per 4-fold higher ACR). Higher ACR was also associated with elevated hfPWV and haPWV (ORs per 4-fold higher ACR were 1.25 [95% CI, 1.12-1.39] for elevated hfPWV and 1.19 [95% CI, 1.06-1.33] for elevated haPWV). Lower eGFR was associated with lower odds of elevated baPWV and faPWV (ORs per 15-mL/min/1.73m2 lower eGFR were 0.92 [95% CI, 0.84-0.99] and 0.91 [95% CI, 0.85-0.99], respectively). Unable to address temporality betweenCKD measures and arterial stiffness. Both lower eGFR and higher ACR are independently associated with measures of central arterial stiffness, with stronger associations for ACR over eGFR. Our findings suggest that central arterial stiffness may be an important pathophysiologic phenotype of vascular disease in CKD.

Decompensated Heart Failure and Renal Failure: What Is the Current Evidence?

Acute decompensated heart failure (ADHF) is one of the biggest challenges in the management of chronic heart failure. Despite several advances in medical and device therapy, high readmission and mortality rates continue to be a burden on healthcare systems worldwide. The aim of the current review is to provide an overview on current as well as future approaches in cardiorenal interactions in patients with ADHF. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction, referred to as cardiorenal syndromes (CRS) or cardiorenal interactions. Patients with ADHF frequently develop worsening of renal function (WRF) and/or acute kidney injury (AKI). Recent studies brought new information about biomarkers in diagnosing and predicting prognosis of CRS. Among others, dry weight at hospital discharge is considered a surrogate marker of successful treatment in ADHF patients with/without renal dysfunction. The etiology of WRF appears to be an important factor for determining risk related to WRF as well as clinical management. The hypertonic saline used as adjunctive therapy for intravenous loop diuretics and/or induction of aquaresis (e.g., using tolvaptan) may be promising and efficient approaches in the future.

Selective abdominal venous congestion to investigate cardiorenal interactions in a rat model.

Abdominal congestion may play an important role in the cardiorenal syndrome and has been demonstrated to drive disease progression. An animal model for abdominal congestion, without other culprit mechanisms that are often present in patients such as low cardiac output or chronic kidney disease, might be interesting to allow a better study of the pathophysiology of the cardiorenal syndrome. The objective of this study was to develop a clinically relevant and valid rat model with abdominal venous congestion and without pre-existing heart and/or kidney dysfunction. To do so, a permanent surgical constriction (20 Gauge) of the thoracic inferior vena cava (IVC) was applied in male Sprague Dawley rats (IVCc, n = 7), which were compared to sham-operated rats (SHAM, n = 6). Twelve weeks after surgery, abdominal venous pressure (mean: 13.8 vs 4.9 mmHg, p < 0.01), plasma creatinine (p < 0.05), plasma cystatin c (p < 0.01), urinary albumin (p < 0.05), glomerular surface area (p < 0.01) and width of Bowman’s space (p < 0.05) of the IVCc group were significantly increased compared to the SHAM group for a comparable absolute body weight between groups (559 vs 530g, respectively, p = 0.73). Conventional cardiac echocardiographic and hemodynamic parameters did not differ significantly between both groups, indicating that cardiac function was not compromised by the surgery. In conclusion, we demonstrate that constriction of the thoracic IVC in adult rats is feasible and significantly increases the abdominal venous pressure to a clinically relevant level, thereby inducing abdominal venous congestion.

Inflammation and Cardio-Renal Interactions in Heart Failure: A Potential Role for Interleukin-6

Introduction: Inflammation is considered a key driver of cardio-renal dysfunction in patients with heart failure (HF). Of the myriad of pro-inflammatory cytokines, interleukin 6 (IL-6) is of particular interest; it is a multifunctional effector with a central role in several chronic inflammatory conditions via its influence on ubiquitous cellular pathways. Accordingly, IL-6 has emerged as a promising therapeutic target for several chronic inflammatory states. Whereas IL-6 causes adverse cardio-renal effects in rodent models, its effects on these pathways in humans are less clear. Hypothesis: Plasma and urine IL-6 levels would associate with key parameters of cardio-renal dysfunction such as diuretic resistance, renal filtration, and neurohormonal activation. Methods: We enrolled 98 consecutive patients receiving high-dose loop diuretics in an ambulatory HF unit. IL-6 levels in plasma were used to query systemic inflammation and IL-6 in urine to quantify inflammation at the renal tissue level. Results: Plasma and urine IL-6 levels were modestly correlated (r = 0.40, P < .001), and levels showed varied association with key parameters of cardiorenal syndrome (Fig. 1). Plasma IL-6, a measure of systemic inflammation, showed the strongest relationship with systemic neurohormonal activation (OR for high plasma renin = 1.9 per SD increase, 95% CI 1.2–3.0, P = .008) and risk of mortality (adjusted HR = 2.3 per SD increase, 95% CI = 1.5–3.7, P < .001). Conversely, levels of urine IL-6, which reported on tissue specific inflammation, were closely associated with measures of cardio-renal dysfunction such as diuretic resistance (OR = 2.3 per SD increase, 95% CI 1.4–3.8, P = .001), lower eGFR (OR = 1.9 per SD increase, 95% CI = 1.2–3.1, P = .01) and increased renal tissue-level neurohormonal activation (OR for high urine renin = 2.1 per SD increase, 95% CI 1.3–3.4, P = .002). Conclusion: IL-6 was strongly and independently associated with parameters of cardio-renal dysfunction, neurohormonal activation, and mortality. In the context of existing mechanistic data suggesting a causal role for IL-6 in cardio-renal dysfunction, this pathway represents a potential therapeutic target.

Insights into cardiorenal interactions in acute decompensated heart failure.

Acute decompensated heart failure (ADHF) is one of the biggest challenges in the management of chronic heart failure. Despite the advances in medical and device therapy, high readmission and mortality rates continue to be a burden on healthcare systems worldwide. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction, referred to as cardiorenal syndrome (CRS) type 1. This review discusses some of the recently introduced findings related to the pathophysiology, diagnosis, and management of this disorder. There is a better understanding of the pathophysiology of ADHF and CRS. Systemic and intrarenal hemodynamic data provided a much deeper insight into various mechanisms of interaction between the heart and the kidney. Novel biomarkers have been discovered and developed recently to help diagnose and predict prognosis of CRS. Although there was optimism toward using ultrafiltration in treating ADHF with CRS, recent data did not support that, and management remains primarily driven by reversing ADHF hemodynamic and neurohormonal derangements. ADHF with CRS carries poor prognosis and high mortality. There is a need for individual risk assessment and management. A dedicated experienced multidisciplinary team is needed to diagnose and manage patients with this problem. Different approaches are needed to address the complex elements of this disorder.

Renal sodium avidity in heart failure: from pathophysiology to treatment strategies.

Increased neurohumoral stimulation resulting in excessive sodium avidity and extracellular volume overload are hallmark features of decompensated heart failure. Especially in case of concomitant renal dysfunction, the kidneys often fail to elicit effective natriuresis. While assessment of renal function is generally performed by measuring serum creatinine-a surrogate for glomerular filtration-, this only represents part of the nephron's function. Alterations in tubular sodium handling are at least equally important in the development of volume overload and congestion. Venous congestion and neurohumoral activation in advanced HF further promote renal sodium and water retention. Interestingly, early on, before clinical signs of heart failure are evident, intrinsic renal derangements already impair natriuresis. This clinical review discusses the importance of heart failure (HF) induced changes in different nephron segments. A better understanding of cardiorenal interactions which ultimately result in sodium avidity in HF might help to treat and prevent congestion in chronic and acute HF.

Relaxin Ameliorates Renal Fibrosis and Expression of Endothelial Cell Transition Markers in Rats of Isoproterenol-Induced Heart Failure.

There may be cardio-renal interactions in rats of isoproterenol-induced heart failure, which may be associated with renal fibrosis and endothelial-to-mesenchymal transition (EndMT). Since its discovery, relaxin (RLX) which was regarded as a reproductive hormone for a long time, is recently considered an effective antifibrotic hormone in cardiac and renal fibrosis. We studied whether RLX diminished renal fibrosis in rats of isoproterenol (Iso)-induced heart failure and investigated the mechanism. Fifty male Sprague-Dawley rats were separated into five groups for treatment: control; Iso subcutaneously injection to induce heart failure, which led to renal fibrosis; RLX subcutaneously injection at low, medium and high dose (0.2, 2, 20 µg·kg-1·d-1 for 21 d). Indices of cardiac function and organ fibrosis were examined. Expression and changes in levels of collagen, cluster of differentiation 31 (CD31), α-smooth muscle actin (SMA), and transforming growth factor β (TGF-β) were measured in renal tissues. In rats with heart failure induced by Iso, treatment with RLX significantly ameliorated cardiac function and inhibited cardiac and renal fibrosis. RLX decreased renal collagen types I and III deposition, increased CD31 expression, and decreased the expression of α-SMA and TGF-β, thereby possibly indicating inhibited renal EndMT in kidneys. Iso-induced heart and renal fibrosis was inhibited even greater with high-dose RLX, so the antifibrotic effect of RLX may be dose-related. In conclusion, RLX may ameliorate renal fibrosis in rats of Iso-induced heart failure, and it is infered that prevention of the EndMT may be one of the possible potential signaling pathways.

Impact of Chronic Kidney Disease on Risk for Vascular Events.

Chronic kidney disease (CKD) accounts for a significant proportion of the morbidity and mortality in the United States. CKD is defined as glomerular filtration rate (GFR) <60ml/min/1.73m2 or clear evidence of renal damage from biopsy. All-cause cardiovascular risk increases with decreasing GFR. Clinically, detection of CKD is through changes in creatinine clearance which estimates GFR, an indicator of kidney function. We reviewed conventional and nonconventional cardiovascular risk factors associated with CKD. Clinically, we reviewed the status of statins as a treatment option for CKD-induced dyslipidemia. CKD has dramatic consequences on cardiovascular risk profile due to a complex pathophysiologic response to declining kidney function. In this review, we explored new, more accurate methods of detecting decreasing kidney function, discerned risk factors for the development of cardiovascular events, and examined the controversial use of statins for renoprotection. Detection of declining renal function by monitoring creatinine has been the clinical gold standard, but it substantially fluctuates with muscle mass, sex, and ethnicity. Newer methods using cystatin C have been at the forefront as the next substance that will be used for detection of CKD. Traditional and non-traditional risk factors contribute to the cardiovascular risk profile of patients with declining renal function. Statins, along with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)s, have been used for renoprotection, but evidence shows only modest benefits in non-dialysis patients. Cardio-renal interaction involves multiple risk factors that contribute significantly to the CKD-induced development of accelerated atherosclerosis, an inflammatory state that causes cardiovascular events.

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) in postcardiotomy cardiogenic shock: how much pump flow is enough?

Post-cardiotomy cardiogenic shock (PCCS) is a complication of heart surgery associated with a poor prognosis: veno-arterial extracorporeal membrane oxygenation (VA ECMO) ensures end-organ perfusion while fully replacing heart and lung function, though it is associated with unsatisfactory results. Few studies have identified reliable predictors of poor prognosis early in the course of extracorporeal support. A recent study showed the strong prognostic power of urine output in the first 24 hours of VA ECMO in predicting early and late mortality of PCCS. Urine output is a commonly collected parameter in all intensive care units (ICU) and has a defined role in the diagnosis of acute kidney injury (AKI) and is inexpensive. These findings offer the possibility to summarize some aspects regarding the adequacy of extracorporeal support early in the course of cardiogenic shock and to shed light about cardio-renal interactions in ECMO patients. Finally, it is our opinion that a timely implantation of mechanical circulatory support in post cardiotomy shock should be considered if systemic perfusion is not ensured by low or medium dose inotropic support and intra-aortic balloon counterpulsation.

Mitochondrial Dysfunction in Cardiorenal Syndrome.

Acute kidney injury (AKI) has a significant impact on the outcomes of critically ill patients, although no effective and specific treatment against AKI is currently available in the clinical setting. It is assumed that reactive oxygen species production by the mitochondria plays a crucial role in renal damage especially caused by cellular apoptosis. Mitochondrial injury in the heart is reported as an important determinant of myocardial contractility. Clinical epidemiological data indicate that remote organ effects induced by AKI, especially organ cross talk between the kidney and heart, might contribute to the poor outcome of AKI patients. Cardiorenal syndrome (CRS) has recently been defined based on clinical observations that acute and chronic heart failure causes kidney injury and AKI and that chronic kidney disease worsens heart diseases. Possible pathways that connect these two organs have been suggested; however, the precise mechanisms are still unclarified. Mitochondrial injury in the kidney and heart has been shown as a crucial pathway of AKI and acute heart failure by several animal studies. Clinical evidence clearly shows cardiorenal interactions in clinically ill patients, but evidence for distant organ effects of AKI on the heart is lacking. We recently found dysregulation of mitochondrial dynamics caused by increased Drp1 expression and cellular apoptosis of the heart in an experimental AKI animal model of renal ischemia-reperfusion. Precise mechanisms that induce cardiac mitochondrial injury in AKI remain unclarified. A recently suggested concept of mitochondrial hormesis may need to be considered in chronic cardiorenal interaction. Identifying the role of mitochondrial injury for CRS will enable the development of novel interventional approaches to reduce mortality associated with AKI. Antioxid. Redox Signal. 25, 200-207.

CARDIORENAL INTERACTION IN DECOMPENSATED CHRONIC HEART FAILURE

Aim. To investigate the prevalence of cardiorenal interactions, predictors of development, variants of clinical course, and outcomes of acute kidney injury (AKI) in patients with acute decompensation of chronic heart failure (ADCHF). Material and methods. Patients (n=278) with clinical manifestations of ADCHF were included into the study. All patients underwent clinical, laboratory and instrumental investigation. Renal function was assessed using the CKD-EPI formula to calculate glomerular filtration rate (GFR). Hydration was assessed using the bioimpedance analyzer ABC-01 Medass (Russia). Chronic kidney disease (CKD) and AKI were diagnosed according to the criteria of the latest Russian and international guidelines. Six phenotypes of AKI were identified: outpatient and hospital acquired, transient and persistent, de novo, and on the background of CKD. Results. CKD was detected in 125 (45%) patients. AKI developed in 121 (43.5%) patients, and in 52.9% of cases was nosocomial, in 53.7% transient and in 52.1% of cases occurred in patients without history of CKD. The risk of in-hospital mortality compared with patients without AKI significantly increased only in patients with nosocomial AKI (14.1 and 3.8%, p<0.05), AKI de novo (14.3 and 3.85%, p <0.05) and persistent (25 and 3.8%, p<0.001). Patients with these variants of AKI as compared to patients without AKI had more pronounced hydration, as well as less frequent prescription of loop diuretics and beta-blockers during outpatient treatment. Conclusion. The high rate (67.6%) of cardiorenal interactions was found out in patients admitted to hospital with ADCHF. Unfavorable prognostic phenotypes of AKI were hospital acquired, persistent AKI and AKI de novo. Patients with these phenotypes had a more pronounced hydration and inadequate outpatient therapy.